Lamotrigine and other therapy-associated HLH syndromes: a review

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation that can occur secondary to medical interventions including immunomodulatory therapies such as immune checkpoint inhibitors and stem cell transplantation. However, lamotrigine and other anti-seizure medications (ASMs), which are not thought of as overtly immunogenic, are an important emerging cause and exploring the pathophysiology of lamotrigine-associated HLH may improve our understanding of secondary HLH. AREAS COVERED: We completed a literature search in EMBASE and MEDLINE for English language articles indexed between 1 January 1966, and 31 August 2025. We review the current understanding of the diagnosis and pathophysiology of known causes of immunomodulatory therapy-associated HLH including chimeric antigen receptor T-cell (CAR-T) therapy and immune checkpoint inhibitors. We then discuss the clinical overlap between ASM-induced HLH & drug-induced hypersensitivity syndrome (DIHS) and explore underlying immune pathophysiology including mechanisms and potential contributors including host genetic factors and viral etiologies. EXPERT COMMENTARY: Lamotrigine-induced HLH has significant clinical overlap with DIHS, with common features of fever, diffuse skin rash, and multi-organ failure. Further advances in immune profiling of patients with ASM-associated HLH will improve our understanding of the pathogenesis and promote the development of novel immunotherapy agents for the treatment of the condition.